The objectives of this proposal are to study the mechanism(s) of action for polyhalogenated aromatic hydrocarbon toxicity and to relate this knowledge to the polybrominated biphenyl (PBB) incident in Michigan. We are proposing that PBB belongs to a specific class of toxic polyhalogenated aromatic hydrocarbons, best exemplified by the most toxic member of the group, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and that toxicity is somehow medicated by a cytoplasmic binding protein involved in the induction of a number of enzymes. PBB congeners which induce a specific group of enzymes are toxic. Enzyme induction may not cause toxicity but nay be somehow related. We propose that prolonged induction, or hyperinduction, caused by prolonged occupation of the receptor's binding site may cause toxicity. Binding by the receptor would not normally cause toxicity if the ligand were metabolized such that it could dissociate from the receptor. Thus rapidly metabolized ligands are not toxic (3-methylcholanthrene could be an example), very slowly metabolized ligands show great variations in response due to differences in rates of metabolism (TCDD may be the example), and ligands, like certain PBB congeners, which are not metabolized do not show variations in toxicity which are related to metabolism. Another type of variation in response to these compounds would be due to mutations which result in the synthesis of binding proteins with much less affinity for the polyhalogenated aromatic hydrocarbons. The non-responsive strains of mice would be examples of this type. We also propose that since the toxic PBB congeners cannot be metabolized their retention in the body in certain cases might be affected by the high affinity binding protein. We further propose that human health effects might correlate with the toxic congeners of fireMaster rather than with the major component, which we now know does not display the toxicity signs usually associated with this class of toxins. The specific aims of the proposed research are to study, determine, or compare: (1) The toxicity of TCDD and 3,4,5,3',4',5'-HexBB in responsive and non-responsive mice. (2) The metabolism and toxicity of the receptor binding constants for TCDD and PBB in guinea pigs, rats, mice and hamsters. (3) The tissue half-lives of 2,4,5,2',4',5'-HexBB and 3,4,5,3',4',5'-HexBB in responsive versus non-responsive mice. (4) Interactions between TCDD and PBB. (5) The Pharmacokinetics of PBB congeners in humans.